This is an application for a NIDA Independent Scientist Award (K02). The candidate, Amelia J. Eisch, Ph.D., is an Assistant Professor in her sixth year on the psychiatry faculty at UT Southwestern Medical Center in Dallas. Throughout her career, Dr. Eisch has established a strong record of publications (39 total; 17 from her independent laboratory), awards and funding from both federal (4 from NIDA, 1 from NIA, 1 from NIMH, 1 from NSF) and non-federal (2 from NARSAD, 2 from Stanley Foundation) sources, and mentoring. Since joining the UT Southwestern faculty in 2000, Dr. Eisch has developed a unique research program with a focus on understanding mechanisms underlying the potent negative impact of drugs of abuse on the hippocampus, particularly on adult hippocampal neurogenesis. However, increasing administrative and teaching obligations have hampered Dr. Eisch's research progress, such that she is able to only devote 50% of her time on research. The receipt of a K02 award would remove or restrict these obligations, thus allowing Dr. Eisch (1) to advance her work on the impact of opiates on adult hippocampal neurogenesis; (2) to nurture a newly-developed collaboration on the role of Cdk5 in adult hippocampal neurogenesis; (3) to learn the principals and practice of cutting-edge techniques (fluorescent activated cell sorting, microarray analysis, laser capture microdissection, retrovirus production, and biochemical and neurosphere assays) from UT Southwestern colleagues, and apply them to her research; (4) to use her newly-developed nestin-CreER12 mouse model to its maximum potential for elucidating the impact of drugs of abuse on hippocampal structure; (5) to generate sufficient data for a series of grant applications, and the time to prepare them: a competitive renewal application for her existing R01, a new NIDA R01 application, and an additional small or exploratory grant application, also to NIDA; (5) to spend more time mentoring and interacting with the six graduate students and two postdoctoral fellows in her laboratory; and (6) to engage collaborators from both inside and outside the addiction field in research on hippocampal neuroplasticity induced by drugs of abuse. The stability and protected time offered by this K02 award would ultimately support two new projects exploring the complex relationship between drugs of abuse, adult neural stem cells, and the hippocampal environment in which these cells proliferate. As such, these studies hold great potential to improve our understanding of the complex mechanisms by which drugs of abuse affect brain function, and therefore may open new avenues for treatment of addiction and relapse to drug seeking. These studies will also shed much-needed light on how adult neural stem cells adapt to chronic exposure of a drug of abuse, and thus will be important to future efforts to harness neural stem cells for repair of the injured, even addicted, brain. [unreadable] [unreadable] [unreadable]